From a drug discovery perspective, carbohydrate pyranose and furanose rings and their derivatives are well suited as templates. Each sugar represents a three-dimensional scaffold to which a variety of substituents can be attached, usually via a scaffold hydroxyl group, although occasionally a scaffold carboxyl or amino group may be present for substitution. By varying the substituents, their relative position on the sugar scaffold, and the type of sugar to which the substituents are coupled, numerous highly diverse structures are obtainable. An important feature to note with carbohydrates, is that molecular diversity is achieved not only in the type of substituents, but also in the three dimensional presentation. The different stereoisomers of carbohydrates that occur naturally (examples include glucose, galactose, mannose etc, FIG. 1), offer the inherent structural advantage of providing alternative presentation of substituents.

FIG. 1
The first example of a combinatorial approach employing carbohydrate chemistry, was a symposium report on the design and synthesis of a peptidomimetic using a glucose scaffold in the early 1990's1. The results, revealed that the glucose based structures designed as mimetics of a potent somatostatin (SRIF) agonist acted as agonists at low concentration, and at high concentration became the first known antagonists of SRIF. Although hardly the production of a library, the results were unique.
Continuing in part the work commenced in the early 1990's, Nicolaou and co-workers began developing carbohydrate based peptido-mimetics targeting integrins. Many integrins recognize an Arg-Gly-Asp (RGD) sequence in ligands such as fibronectin, vitronectin and fibrinogen, each binding with different affinities to the individual integrin receptors. Through a process of rational design a number of carbohydrate based RGD mimetics were synthesized. The chemical synthesis of nine different compounds by this group with very few common intermediates required a considerable amount of chemical effort. It was evident from such results, that in order to generate a number of different structures in a facile manner new chemistries needed to be developed to streamline and enable what at this stage was unfortunately a protracted and arduous methodology.
Since 1998 researchers in the group of Kunz2 have been developing a number of carbohydrate building blocks with a similar purpose in mind. In general the building blocks that they have developed are coupled to a solid support to effect the desired chemical transformations. The chemistry developed can be employed to achieve, like the work of Hirschmann and co-workers3, the introduction of peptidomimetic side chains to carbohydrate scaffolds in an effort to produce glyco-based mimetics of cyclic peptides. Admittedly, with the chemistry they have developed, there are inherent limitations in the types of functional groups that they are able to introduce and the range of stereoisomeric building blocks that they are able to employ.
It is now becoming reasonably established in the art that relates to the solid phase production of combinatorial carbohydrate based libraries, that one of five protecting groups on a carbohydrate scaffold is a protecting group modified as a linker, so as to allow coupling of the block to a solid support. The strategy that then follows is simple, remove a protecting group and effect coupling at the freed functionality with a peptidomimetic or other reagent. Remove another protecting group and couple with the next reagent, and so on.
Following this generally accepted principle, a system has been developed that allows the chemical synthesis of highly structurally and functionally diverse derivatised carbohydrate and tetrahydropyran structures, of both natural and unnatural origin. The diversity accessible is particularly augmented by the juxtaposition of both structural and functional aspects of the molecules. In order to access a wide range of diverse structures, stereo-center inversion chemistry is required, so as to achieve non-naturally occurring and hard to get sugars in a facile manner. Other chemistries are also required that provide unnatural deoxy or deoxy amino derivative which impart greater structural stability to the drug-like target molecules. With a suite of reagents to effect a suitable range of chemistries on a solid support, allowing such things as; wide functional diversity, highly conserved intermediates, a limited number of common building block to be required, and with suitable chemistry to allow access to unusual carbohydrate stereo-representations and including access to deoxy and deoxy amino analogues, a methodology is then established that can create focused libraries for a known target, or alternatively diversity libraries for unknown targets for random screening.
Many of the traditional methods of carbohydrate synthesis have proved to be unsuitable to a combinatorial approach, particularly because modem high-throughput synthetic systems require that procedures to be readily automatable. The compounds and processes described herein are particularly suited to the solid and solution phase combinatorial synthesis of carbohydrate-based libraries, and are amenable to automation. The methods of the invention yield common intermediates that are suitably functionalized to provide diversity in the structure of the compounds so generated. In this way the technology described can produce many and varied compounds around the basic structure shown in FIG. 1. Using this method, it is possible to introduce varied functionality in order to modulate both the biological activity and pharmacological properties of the compounds generated.
Thus the compounds and methods disclosed herein provide the ability to produce random or focused combinatorial-type libraries for the discovery of other novel drug or drug-like compounds, or compounds with other useful properties in an industrially practical manner.
It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.